A Novel Human Glucocorticoid Receptor Variant, G459V, is Hyperactive in Response to Steroids

A potential cause of the variable response to injury and sepsis is the variability of a patient's human glucocorticoid receptor (hGR) profile. To identify hGR variants, blood samples were collected on admission and biweekly thereafter from hospitalized patients who sustained at least a 20% total body surface area burn injury. A hyperactive G1376T single-nucleotide polymorphism (SNP) isoform was identified. This SNP led to a single amino acid change of glutamine to valine at site 459, "G459V," in the DNA-binding domain. The isoform's activity was tested in a reporter assay after treatment with steroids, the hGR antagonist RU486 (mifepristone) alone, or RU486 followed by steroids. When treated with hydrocortisone, the hGR G459V isoform had a hyperactive response; its activity was over 30 times greater than the reference hGRα. Unexpectedly, G459V had significantly increased activity when treated with the hGR antagonist RU486. With the combination of both RU486 and hydrocortisone, G459V activity was repressed, but greater than that of RU486 alone. Finally, when hGRα was cotransfected with G459V to simulate isoform interaction, the activity was closer to that of the hGRα profile than the G459V isoform. The unique activity of the G459V isoform shows that some variants of hGR have the potential to alter a person's response to stress and steroid treatment and may be a factor as to why mitigating the clinical response to sepsis and other stressors has been so elusive.